C–N cross-coupling is one of the most valuable and widespread transformations in organic synthesis. Largely dominated by Pd- and Cu-based catalytic systems, it has proven to be a staple transformation for those in both academia and industry. The current study presents the development and mechanistic understanding of an electrochemically driven, Ni-catalyzed method for achieving this reaction of high strategic importance. Through a series of electrochemical, computational, kinetic, and empirical experiments, the key mechanistic features of this reaction have been unraveled, leading to a second generation set of conditions that is applicable to a broad range of aryl halides and amine nucleophiles including complex examples on oligopeptides, medicinally relevant heterocycles, natural products, and sugars. Full disclosure of the current limitations and procedures for both batch and flow scale-ups (100 g) are also described.

It goes both ways: A thiol-reactive cross-linker based on a bridged azobenzene derivative permits photoreversible control of peptide conformation on irradiation with violet (407 nm) and green (500-550 nm) light (see picture) through isomerization of the cross-linker. The large separation of the absorbance bands of the cis (yellow) and trans (red) isomers enables complete bidirectional photoswitching.

Using an alanine-scanning method, we have found that the antibacterial and hemolytic activities of the amphipathic cyclic decapeptide antibiotic tyrocidine A depend on different structural components. Single substitution of glutamine-6 of the natural product with a cationic amino acid results in a therapeutic index enhancement of up to 140-fold. Successful dissociation of the two intimately associated properties should enable discovery of novel analogues with both high bacterial selectivity and antibacterial potency to counter microbial resistance.

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A simple and efficient preparation of gramicidin S and its analogues is described. It involves solid-phase peptide synthesis and on-resin macrolactamization without side chain protection, affording cyclic products in high yield and high purity. The high specificity of the cyclization reaction was shown to originate in the formation of a pre-organized conformation of the linear biosynthetic precursor of gramicidin S. This facile method will provide convenient access to the analogues of the natural product for functional optimization to counter microbial resistance.

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A previously developed method for cyclic peptide synthesis was demonstrated to be able to provide convenient access to large combinatorial libraries of analogues, and this methodology was applied to the optimization of natural product cyclic decapeptides. Using this method, a 192-member library was designed and successfully constructed on the basis of the natural products tyrocidines, streptocidins, and loloatins to increase the therapeutic indices of these antibiotics. Library screening identified nine analogues whose therapeutic indices were increased by up to 90-fold in comparison to the natural products. Three of these analogues showed significant increase in antibacterial potency and concurrent drastic decrease in hemolytic activity. Since the natural products target the bacterial cell wall, the newly discovered analogues are promising leads for drug development against drug-resistant bacteria.